IntroIn 2013, Evolutionary Muse rocked the industry by releasing the first product designed to cause white adipocytes to convert into BRITE adipocytes. Aptly named BRITE, these adipocytes are named for being BROWN IN WHITE cells—white adipocytes which behave like brown adipocytes. Brown adipocytes are metabolically active cells which, unlike white adipocytes, use their fat stores to generate body heat. Long thought to be non-existent or very rare in humans, brown adipocytes were discovered to be quite active, though through evolution, environmental mastery (i.e., comfortable living via climate control), and more than adequate dietary satisfaction (leading to its own hormonal milieu), brown fat activation became almost dormant. This brown fat:white fat reduction has instead led to massive insulin resistance, leptin chaos, and major obesity.
With years more painstaking research, Evolutionary Muse has once again taken huge leaps forward, finally perfecting a formula that is easily encapsulated in a powdered version, while delivering a powerhouse formula that triggers a huge shift in damaging white fat towards metabolically hyperactive BRITE fat.
Difference between WAT and BATBrown Adipose Tissue (BAT) is abundant in small mammals like rodents, as well as newborn humans, and is thought to offer an evolutionary protection against cold temperatures to increase survival rate. BAT works quite differently, if not opposite, to White Adipose Tissue (WAT). BAT is dense in mitochondria and considered a highly thermogenic fat cell, responsible for creating heat through a process called "non-shivering thermogenesis”. This process burns calories through a futile cycle of shuttling protons to the mitochondria to generate heat. WAT, however, is what we all think of when we hear the term "body fat”. It stores calories so they can be used later during periods of hunger or famine, and secretes various adipokines. This is a crucial part of our physiology, and we would not exist today without it. But these WAT cells can become dysfunctional (for genetic reasons, poor diet, lack of exercise, etc.) and get too good at storing fat.
It was previously thought that adult humans have an inconsequential amount of BAT. In recent years, however, it has been determined that we have more than originally thought. We have also learned that we don’t need a large volume of these cells to have a significant impact.
Even more recently, we have discovered another player in the adipocyte story—Brown-In-White cells, or "BRITE”. At a microscopic level, these cells display a color between brown and white, and behave in a similar thermogenic fashion to BAT cells. They are also known as beige, inducible, recruitable-brown, and brown adipocyte-like cells, but we will refer to them as beige/brite moving forward.
The research on brite cells is still in early stages, but we now know enough about how they are formed and the metabolic advantage they are capable of providing that we can target them as a viable and important angle in weight management and metabolic optimization. UCP1 expressing adipocytes are lower in obese and older subjects. While we don’t know yet if reduced thermogenic activity is a cause or consequence of obesity, we do know that an increase in BAT and/or brite cells improves glucose tolerance and insulin sensitivity.
Two distinct pathways exist towards increasing brite cells in adult humans, (1) triggering precursor cells into becoming brite cells, and (2) turning mature WAT cells into brite cells. We want to target these pathways directly so that we can increase the ratio of brite cells to WAT cells, allowing your body to constantly burn more calories.
Let’s dive into some of the known methods of brite cell creation and activation.
Irisin and PGC-1alphaExercise causes increased expression in muscle of PPARg coactivator 1-alpha (PGC-1a), which downstream results in a hormone/myokine called irisin. This irisin contributes to a browning of WAT cells. So not only does exercise burn calories directly, but also secondarily through triggering the browning process with irisin. Fortunately, this is an exploitable angle independent of exercise by triggering the PPARg cascade.
Cold Therapy, B3 adrenergic activatorsCold exposure triggers macrophages in BAT to produce catecholamines like norepinephrine (NE). NE agonizes b-adrenergic receptors on fat cells. Cold also activates beige cell development and function. The effect can be mimicked with b3 adrenergic activators, which also trigger PGC-1a and brite cell development. It can also be mimicked with TRPM, or cold-sensor activators.
PRDM16, BMP-7Prdm16 is a transcriptional cofactor, substantially enriched in human BAT compared to adjacent WAT. It acts by binding to and modulating other factors like C/EBPb, PPARy, PPARa, and the aforementioned PGC-1a. Knocking out Prdm16 negates the thermogenic effect of brown cells, and increases WAT. Considered a key driver of brown fat cell fate, this cofactor is quite important. Bone Morphogenetic Protein-7 (BMP-7) increases expression of Prdm16 in precursor cells, and is essential for brown fat development. BMP-7 is fortunately something we can target with supplementation.
Adenylyl Cyclase (AC) and Alpha-1 adrenergic activationAC is an enzyme that catalyzes the conversion of ATP to cyclic AMP. We mentioned beta-adrenergic receptor agonism, but it turns out this is greatly enhanced with simultaneous AC upregulation and alpha-1 activation. So targeting AC, alpha-1, and beta-adrenergic agonism together causes enhanced brite cell creation.
UCP1BAT mitochondria respond to something called UCP1 (uncoupling protein 1) to burn fat and generate heat, while brite cells seem to express lower levels of UCP1. However, brite cells potentially burn fat independently of UCP1 signaling, and furthermore, with the proper triggers, brite fat can actually turn on high levels of UCP1. Multiple ingredients in the BRITE™ formula will encourage WAT cells to upregulate UCP1 levels.
Some of you may be familiar with a somewhat popular drug in the bodybuilding community years ago called DNP (which actually has roots in the 1930s as a weight loss drug). DNP was meant to mimic activated UCP1, which drastically elevated thermogenesis. While extremely effective, unregulated uncoupling can (and did) cause hyperthermia and death. Fortunately, we now have effective ways of targeting UCP1 safely.
Ingredients and Function
Butcher’s Broom ExtractButcher’s Broom is an herb, also known as Ruscus aculeatus. It gets its name from the practice of butchers using it for its supposed antibacterial properties to clean their cutting boards. It has been used in traditional medicine for its vasoconstrictive and anti-inflammatory actions (reducing swelling, preventing hemorrhoids, etc).
The plant contains a variety of saponins, which have been shown to activate alpha-1 adrenergic receptors and stimulate the release of norepinephrine. It also has a protective effect on capillaries, strengthens blood vessels, and helps maintain healthy circulation (1).
As discussed previously, this alpha-1 activation is important and has been shown to shift preadipocytes to beige cells as opposed to white adipose tissue (2).
We previously discussed the adenylyl cyclase angle, which forskolin has been shown to activate. Forskolin also potentiates AC activation from endogenous hormones (3,4). Forskolin also stimulates alpha-1 adrenergic receptors like Butcher’s Broom. Additionally, the alpha-1 stimulation greatly enhances the potency of the yet to be discussed beta receptor agonists in the formula (5).
FucoxanthinFucoxanthin targets our uncoupling protein angle, by inducing and/or upregulating UCP1 expression in WAT. As a bonus, it also regulates unfavorable cytokine secretion in WAT, which improves blood glucose regulation and insulin sensitivity (6–8).
OctopamineAs mentioned earlier, b3 adrenergic activation is crucial for converting WAT to beige cells. Octopamine is a specific ligand for this process in mammals, and is considered to be the most selective of the biogenic amines as a b3-AR agonist (9,10).
Beta-lapachoneB-lapachone is a quinone found in the bark of the lapacho tree. To fully understand the benefit of this ingredient, it will be helpful to learn a new term. A microRNA called "miR-382” inhibits the differentiation of adipocytes into beige adipocytes. It directly opposes PRDM16 that we talked about in the intro. If we upregulate miR-382, we’ve got no chance of beige differentiation. B-lapachone favorably controls the expression of miR-382. Additionally, it increases BAT specific genes during differentiation (including UCP1), stimulates the browning process of WAT, and increases SIRT1, PGC-1a, and PPARa. In rodent studies, this equated to increased resting energy expenditure and decreased body fat (11-13).
AndrographolidesSREBPs are major transcription factors involved in adipogenic differentiation from precursor cells, as well as factors in fat storage. Andrographolides downregulate the expression of SREBPs and target genes in BAT, decreasing fat storage and encouraging differentiation to brite cells. Andrographolides also target the activation of the TRPV4 and TRPV1 receptors. Finally, andrographolides trigger an increase in Wnt/b-catenin signaling, contributing to the WAT browning process (14–17).
Safflower Leaf ExtractBy enhancing angiogenesis through the VEGF signaling pathway, SLE promotes differentiation from precursor cells away from the WAT pathway.
Several studies have looked at the effect of SLE on rodents given obesogenic diets, with a long list of benefits elucidated. By promoting the browning of subcutaneous WAT and activating the IRS1/AKT/GSK3b pathway, the SLE groups saw reduced body fat mass, inflammation, fasting blood glucose, and total cholesterol and triglycerides, with an increase in insulin sensitivity (18–20).
Another study, in addition to reaffirming the above findings, also showed an interesting benefit in gut function by increasing short chain fatty acid production and improving gut microbiota (21).
GypenosidesGypenosides are saponins found in the Jiaogulan plant. This ingredient targets both WAT and BAT. We get WAT browning, and an increase in fat oxidation genes in both WAT and BAT. Obesogenic diet mice treated with gypenosides had a significantly reduced bodyweight vs. control, with lower cholesterol and insulin resistance. Interestingly, similar to Safflower Leaf Extract, research also shows improved gut microbiota with gypenosides supplementation (22).
MentholAside from b3 adrenergic receptor activation, the other most important way to start the browning process of WAT browning, as previously discussed, is through cold exposure. By exposing the body to cold temperatures long term, it activates the TRPM8 receptor, which triggers browning in order to more effectively use WAT to create body warmth (23).
TRPM8 activation also enhances the thermogenic function of brown adipocytes through UCP1 and the b-adrenergic pathway.
Menthol mimics long-term cold exposure by activating the TRPM8 channel, and has been shown to induce WAT browning, as well as an upregulation in BAT thermogenesis. This has been shown to increase core temperature, reduce body fat and improve glucose metabolism (24–26).
PiperonalPiperonal is an active constituent of piper nigrum seeds and also found in vanilla. It has been called a "potent antiobesity agent”, and is another ingredient in the formula that brings the one-two punch of inhibiting preadipocyte differentiation and upregulating thermogenic genes in WAT (27).
In rodents fed obesogenic diets, piperonal did everything you could hope for. It attenuated body fat gain, adipocyte size, glucose and insulin elevation. It stimulated AMPK and elevated circulating adiponectin (28,29).
Black Pepper ExtractTRPV1 is a capsaicin and vanilloid receptor in the body that is responsible for detection and regulation of body temperature and pain. More recently this receptor has been identified as a major player in obesity and body fat regulation. Stimulation of TRPV1 has been shown to upregulate BAT and increase fat oxidation and energy expenditure. TRPA1 is a similar receptor that functions to recognize cold and pain.
Piperine, as well as several other compounds in black pepper have been shown to be TRPV1 and TRPA1 agonists, with an even greater efficacy than capsaicin (30,31).
Bitter Melon Seed PowderBitter Melon Seed contains CLnA (conjugated linolenic acid), and AEA (a-Eleostearic acid), both of which contribute to fat burning. BMS has also been shown in multiple studies to upregulate mitochondrial biogenesis and UCP1, and has a direct browning effect on WAT cells (32–41).
Trans-CinnamaldehydeTrans-Cinnamaldehyde is a pungent compound from cinnamon or dried cassia bark. TC has been shown to increase UCP1 in both WAT and BAT, inducing browning of WAT cells. It also activates the cold receptor TRPA1. Back to those rodents fed obesogenic diets, TC inhibited hypertrophy of adipose cells, decreased body fat (including visceral fat), decreased voluntary food intake, and improved insulin sensitivity (42,43).
Wasabi Leaf ExtractFrom the Japanese Wasabi plant, this leaf extract targets body fat loss in a few different ways. One of the most important ways to cause a browning of WAT is through the b3 adrenergic system. WLE has been shown to upregulate expression of the b3 adrenergic receptors in BAT (44).
In multiple studies looking at mice and rats fed an obesogenic diet, groups given WLE showed significantly less body fat. Fat storage markers were suppressed (SREBP-1c, PPARy, C/EBPa), and thermogenic/fat burning markers were enhanced (PPARa, adiponectin, AMPK). Adipose cell hypertrophy was inhibited, and fatty acid oxidation was enhanced (45,46).
Oleuropein (40% Olive Leaf)Oleuropein, or OLE, is a phenol compound found in green olives, olive leaves and argan oil. This compound is well studied and has fat loss benefits coming from numerous angles.
For starters, OLE can help preadipocytes from becoming fat cells by limiting lipid accumulation and actually inhibiting the differentiation process into adipocytes. Similar to WLE, it suppresses SREBP-1c, PPARy and C/EBPa as well as downstream targets (47,48).
Next, OLE activates UCP1 in BAT, increasing thermogenesis. It also agonizes the TRPV1 receptor and b2/3 adrenoreceptors, while increasing epinephrine and norepinephrine (49,50). Additionally, it is a PPARa agonist, and upregulates hormone-sensitive lipase (HSL) in WAT, a key player in fat burning (51).
Several studies have looked at the inclusion of OLE in rodents fed obesogenic diets, and have shown reduced body weight and body fat, triglycerides, cholesterol and leptin, with higher rates of fat oxidation.
Additionally, in a 12-week randomized control trial with 46 people, OLE was shown to improve insulin sensitivity and pancreatic beta cell function (52).
SesamolSesamol is a phenol derivative of sesame oil with antioxidant and anti-inflammatory properties. This is another ingredient in the formula with the aforementioned two-pronged attack. It downregulates adipogenic differentiation factors (C/EBPa, PPARy, SREBP-1), and decreases fat accumulating enzymes like fatty acid synthase (FAS), while upregulating fat oxidizing enzymes like HSL, LPL and AMPK. In mice on an obesogenic diet, it decreased fat mass and adipocyte size in both WAT and BAT by increasing UCP1 and PCG1a (53–55).
Trans-Retinoic AcidTRA is an active metabolite of vitamin A. Animals treated with TRA show a two-fold increase in brown specific genes, creating augmented BAT activation and fat oxidation. It enhances adipose mitochondria and causes WAT to behave in a more metabolically oxidative fashion. It also stimulates irisin secretion (normally released in response to exercise), which encourages adipocyte browning. Finally, we’ve got another ingredient targeting adipocyte differentiation, encouraging non-adipocyte pathways (56–60).
ConclusionAs you can see, we have exhaustively targeted all of the known pathways of creating brite cells in the body through either recruiting precursor cells or converting mature white cells. Regular supplementation should encourage fat loss and mimicking of a lean phenotype acutely, and even more so when taken chronically—as brite cells don’t immediately revert back to white adipose upon cessation of the product. BRITE™ is a long-term solution to an ongoing, serious problem plaguing modern society.
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